Saltatory conduction

Post-publication activity

Curator: Ichiji Tasaki

The process of excitation and conduction in vertebrate myelinated nerve fibers is characterized by its discontinuous and saltatory features. Undoubtedly, these distinguishing features are derived from the following histological and physiological properties of these nerve fibers.

• The myelin sheath which covers the axis-cylinder of these nerve fibers is interrupted more-or-less regularly at every node of Ranvier.
• Flow of electric current in and around these nerve fibers is restricted by insulation of the axis-cylinder with myelin sheath.
• The cortical layer of the axis-cylinder at the node of Ranvier is capable of producing action potentials in an all-or-none manner in response to passage of outwardly-directed electric current.
• The action potential produced at one node of Ranvier generates a pulse of strong outwardly-directed current at the neighboring nodes.

Myelin sheath and nodes of Ranvier

In amphibian nerve fibers of 12 – 15 $$\mu$$m in diameter, the myelin sheath is about 2 $$\mu$$m thick. It consists of a large number (~120) of compact lamellae containing lipids and protein molecules. In living nerve fibers, the gap in the myelin sheath at the node is about 1 $$\mu$$m wide.

Electric insulation of axis-cylinder by myelin sheath

In 1934, shortly after the development of the technique of surgically isolating a motor nerve fiber innervating toad's gastrocnemius muscle in G. Kato's laboratory, a discovery was made by M. Kubo and S. Ono indicating that the myelin sheath exerts a strong influence upon the effectiveness of a stimulating current pulse.

Figure 1: The threshold intensity of a long current pulse for exciting a motor nerve fiber plotted against the distance from the nodes of Ranvier. B represents a battery. The stimulating cathode (pipette electrode of  100 $$\mu$$m in diameter at the tip) was displaced in a shallow pool of saline stepwise along the nerve fiber. The all-or-none muscle twitch was taken as an index of nerve excitation.

By measuring threshold intensities of current pulses delivered to a nerve fiber floating in a shallow pool of saline solution by use of a pipette electrode, it was found that the threshold reaches a sharp minimum when the stimulating cathode is placed close to one of the nodes and a sharp maximum when the electrode tip is at the point halfway between two neighboring nodes. From extensive analyses of this and subsequent experimental findings, the following conclusions are deduced.

• The ohmic resistance of the myelin sheath is very high.
• The excitation process is elicited from a nerve fiber by a flow of outward current at the node.

Capacitive flow of current through myelin sheath

Shortly before World War II, it was found possible to record action currents derived from a short segment of a nerve fiber by dividing the surrounding saline solution into independent pools by use of narrow air-gaps. (See Figure 2.)

Figure 2: Left: Schematic diagram illustrating the setup employed for recording action current from a short (  l mm long) myelinated segment of an isolated nerve fiber and an example of the records obtained. Right: Action current recorded from a short segment including a node of Ranvier. To evoke an impulse conducted through the site of recording, a brief electric shock was delivered to the fiber near its proximal end.

The left-hand record in the figure shows the time-course of the current traversing a short myelinated region of a nerve fiber at the time when an impulse is passing through the region. Note that the interval between the two peaks of the transient outward current coincides with the internodal conduction time (~2mm / 20mm per msec). Evidently, these two peaks are produced by capacitive flow of current through the myelin sheath in association with the onset of an action potential at node $$N_{1}$$ and at $$N_{2}$$ in the top diagram. From this and other related experiments, it is concluded that the myelin sheath behaves like a simple electric capacitor with a high parallel resistance.

Inward current associated with excitation of a node of Ranvier

Figure 2, right, shows the time-course of the action current traversing the surface of a short portion of a nerve fiber including one node of Ranvier ($$N_{1}$$). It is recorded at the time when an impulse is passing through the portion. Evidently, the first upward deflection represents the outwardly-directed current associated with the development of an action potential at the proximal node ($$N_{0}$$).

By examining the effect of an anesthetizing solution added to the distal pool and to the middle pool of saline solution, it was shown that the sharp downward deflection represents the inwardly-directed current initiated by the onset of an action potential at the middle node ($$N_{1}$$) and terminated by the onset of an action potential at the distal node ($$N_{2}$$).

Production of all-or-none action potentials by a single node of Ranvier

Action potentials developed by a single node of Ranvier can be recorded by connecting the distal portion of an isolated nerve fiber to an amplifier with a high input-impedance, followed by anesthetization of all the nodes on the proximal side of the node under study. (See Figure 3.)

Figure 3: Action potentials developed by a single node of Ranvier ($$N_{1}$$) in response to brief rectangular voltage pulses (S) of threshold strengths. V represents the input of an amplifier. Note that both nodes $$N_{0}$$ and $$N_{2}$$ are unexcitable. The durations and voltages of the pulses employed are indicated. (Toad motor nerve fiber at 10°C.)

Here, electric responses are elicited from node $$N_{1}$$ by delivering brief voltage pulses between the pool of normal saline (in which $$N_{1 }$$is immersed) and the proximal portion of the fiber (separated from the pool containing normal saline by a narrow air-gap). The action potentials observed are about 110 mV in amplitude and have an abrupt rising phase and a gradual falling phase, followed finally by a slightly accelerated fall of the potential at the end. Note that full-sized action potentials are produced in an all-or-none manner when the potential inside the node is raised to the threshold level (roughly 20 mV in the present case) by the applied pulses.

Safety margin in nerve conduction

The production of an action potential at one node of a nerve fiber is accompanied by a flow of current circulating locally between the excited node and the neighboring resting node. It has been proven repeatedly that the outward current generated at the neighboring node is far more intense than the level needed for exciting a node in its resting state. In other words, the process of successive re-stimulation of the nodes by the local current (Strömchen, Hermann, 1879) proceeds with a considerable margin of safety. It should be remembered in this connection that the capacitive flow of current through the myelin sheath imposes a strict lower limit on the time required for the excitation process (i.e. abrupt change in e.m.f.) to jump from one node to the next.

Saltatory conduction — A historical narrative

In the winter of 1938, the author (I. Tasaki) was pursuing the study of the effect of anesthetics on isolated single nerve fibers at the physiological laboratory of Keio University in Tokyo. At that time, on the basis of previous experiments on single nerve fibers by use of the technique of tripolar stimulation, there was ample evidence indicating that the nerve fiber is electrically insulated by myelin sheath and also that a propagating nerve impulse is generated by an outward flow of current through the uninsulated surface of the axis-cylinder at the nodes of Ranvier.

On one evening, the author decided to examine the effect of a 3 mM cocaine-Ringer's solution applied to a short portion – including a single node of Ranvier – of a motor nerve fiber-gastrocnemius preparation. To test excitability of the node before and after application of the anesthetic, the technique of tripolar stimulation was adopted as previously done.

[The node under study was separated from its neighboring portions of the fiber by two narrow air-gaps which divide the surrounding Ringer's solution into three discrete pools, and three stimulating electrodes placed in these pools were connected to two separate low-impedance voltage sources].

Immediately after application of the cocaine-Ringer's solution to the single node, it was substantiated that the cocaine concentration used was high enough to render the node under study completely unexcitable. When the effect of a stimulating shock applied to the nerve fiber was tested, it was surprisingly noted, with great excitement, that no block of conduction was brought about by the anesthetizing solution. That is, a nerve impulse evoked in the proximal portion of the fiber was conducted across one totally unexcitable node to the distal portion of the fiber. The following intriguing question arose at once: how can a nerve impulse travel through an unexcitable region of a nerve fiber?

In those days, most physiologists accepted the assumption that nerve impulses travel continuously in the interior of the axis-cylinder. When the surprising experimental fact stated above was brought to light, it became immediately cleat that the validity of this old, widely accepted assumption had to be questioned.

Further experimentation revealed the following facts:

• Any mechanical or osmotic injury inflicted upon the anesthetized region promptly blocks nerve conduction across the region.
• Application of the anesthetizing solution exclusively to the myelinated segment of a nerve fiber does not produce any significant change in the excitability of the fiber.
• When a portion of the fiber that includes two successive nodes is anesthetized, conduction block takes place occasionally.
• When three or more nodes are included in the heavily anesthetized region, no conduction of nerve impulses across the region can be observed.

It was not difficult to gain a reasonable understanding of all these experimental findings. Shortly before these experiments were performed, A L. Hodgkin (1937) examined the mechanism of conduction block induced by mechanical compression of the frog sciatic nerve (trunk) and explained the results obtained on the basis of Hermann's local current theory. It was seen from this that Hermann's theory offers a wholly satisfactory explanation of all of the experimental findings stated above. The explanation advocated is as follows.

"An action potential produced by the node immersed in normal Ringer's solution generates a flow of outwardly-directed current at the neighboring nodes. This current is so strong that, even after undergoing progressive attenuation in the anesthetized region including one or two nodes, it is still capable of exciting the first normal node on the distal side of the anesthetized region. Conduction block takes place when the outward current arising from the proximal normal node becomes subthreshold for the node on the distal side of the anesthetized region."

In fact, by measuring the threshold strengths of test electric shocks applied to the distal node, it was decisively demonstrated that the expected barely subthreshold current is traversing the distal node when conduction block actually takes place. Furthermore, evidence was adduced to show that the salt solution outside the nerve fiber is directly involved as the pathway of the current in the process of re-stimulation of successive nodes. The manuscript describing all of these early observations on saltatory conduction was sent to the USA and was published in the American Journal of Physiology in 1939.

During the following years, the author repeated, confirmed and extended those early observations by recording action currents of isolated single nerve fibers with a cathode-ray oscilloscope which the author himself constructed. When the time for publication of the new results came, a new difficulty arising from the restless world situation at that time had to be overcome. Because it became impossible to seek publication of the new material in the USA, the first two of the manuscripts (written in German) had to be sent to Frankfurt, Germany, via Siberian rail-road. When the Siberian route became unavailable in 1941, the manuscripts were sent to Frankfurt by submarine via South America.

Figure 4: Dr. Ichiji Tasaki. Photo taken in 1954, at a most pivotal time in his career.

A long time after the end of the war, it was found that all of the manuscripts sent to Germany were accepted and published by the Pflügers Archiv. At about that time, news was received in Tokyo that new experiments have been conducted on saltatory conduction by A F.Huxley and R.Stämpfli.

Much later, here at National Institutes of Health, the absolute values of the resistance and capacitance of the myelin sheath and of other parts of the nerve fiber were measured by a reasonably reliable method (1955). Furthermore, the time-course of the action potential developed by a single node of Ranvier could be determined with fair accuracy (1956). These data were found to form a basis of quantitative analysis of the phenomenon of saltatory conduction in myelinated nerve fibers (cf. Tasaki, 1982).

References

Ranvier, L. (1871) Contribution á l'histologie et á la physiologie des nerfs périphériques. C. R. 73, 1168-1171.

Hermann, L. (1879) Handbuch der Physiologie., Theil 1. 1-196, Vogel, Leibzig.

Kato, G. (1934) Microphysiology of Nerve, Maruzen, Tokyo.

Tasaki, I. (1939) Am. J. Physiol. 127: 211-227.

Tasaki, I., and Takeuchi, T, (1941) Pflügers Arch ges. Physiol. 244: 696-711; and (1942) 245; 764-782.

Huxley, A. F., and Stämpfli, R. (1949) J. Physiol. 108: 315-339.

Hodgkin, A. L. (1937) J. Physiol. 90: 183 – 232.

Tasaki, I. (1982) Physiology and Electrochemistry of Nerve Fibers, Academic Press, New York.